Dr. Kennedys comment on Rapa, not completely inhibit mTOR1, seems to support his modulation suggestion. If that’s true it may help our dosing options.
Show me the level of mTOR inhibition in humans on typical rapamycin protocols?
He’s talking about complete mTOR ABLATION models of mice…we know this.
There is absolutely NO WAY a human is going to abolish mTOR without passing out on dose escalation side effects first.
This is a translation myth to concern ourselves with mTOR ablation…we are barely touching it. I counter that we’re nowhere near doing ENOUGH.
You can, as has been post several time.
Cost around $3,000 - $3,500
All standard tracer and equipment
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Meaningless. We already know this. You are sharing a measuring tool, not human data.
Show me the results of a cohort of HUMANS on Rapamycin?
I think we are saying the same thing? I was trying to suggest that may be the low daily dosing would make more sense than pulsed dosing since it is not blocking it completely.
Absolutely, I don’t go to the gym for 3 days after a high dose of rapamycin, because I just don’t feel like it, but I really think after a few days I feel better with high doses than with weekly lower doses.
As I have posted elsewhere, I don’t think young people will have many subjective positive effects from taking rapamycin because they are already young and don’t have much that needs fixing.
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I plan on moving as well, double down twice a week due to extreme fatigue and aches for a couple days-then I am fine. Especially if I take a run or play golf during those days.
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You guys are experiencing fatigue after taking Rapamycin? I am getting an energy boost with my low dose. Is this a temporary effect? I am confused about what is causing your fatigue and trying to comprehend what should be happening to me. Thanks.
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I feel a stimulant effect the first day or so. Resting heart rate a little higher for a day or two. Workouts seem harder to get through and slower recovery, but could be placebo.
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Yes but with every dose it gets less even though I am increasing the dose
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Dr. Green is still recommending weekly dosing (6 mg) to patients.
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Hi Zazim, welcome to the forums. Thanks for updating us with Dr. Green’s current recommendations. Are you taking rapamycin? How’s it going for you?
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I will be starting Rapa in about a week. Based on my research, after an initial bi-weekly ramp up period to find my max tolerable dose, I plan to dose once per month.
I was originally thinking of a 1mg/day dosing strategy for it simplicity and not having to take high dosages at one time. However, it appears that high, intermittent dosing clearly has the best reward/risk ratio. At high continuous dosages the mice lived longer, Rapa crosses the blood brain barrier better, but the side effects are worse. Some mouse studies indicate that intermittent dosing retains the majority of the benefits of continuous dosing. With intermittent dosing I can take much higher dosages with less side effects so this seems like a no brainer to me now.
With regard to intermittency, I don’t feel comfortable with weekly dosing because the long half life of Rapa will still leave a significant amount in my system after one week raising the risk of side effects possibly because of impacts on MTORC2. I am not even comfortable with bi-weekly dosing because I do not want to have MTORC1 inhibited for such a long duration each month and potentially interfere with my workout recovery and ability to put on muscle. Based on what I am hoping to achieve, dosing once per month seems to be the most obvious choice for me to balance out these concerns while still achieving some if not most of the benefits.
In addition, I’ve be researching fasting as a possible way to improve health and extend lifespan. Some studies indicate that the effects on longevity and Rapa may be additive and complementary strategies. As a result, each month I plan to use Rapa to kick off a 4-5 day fast mimicking diet as it appears they should complement one another well.
Anyway, this is my argument for a once monthly dosing schedule and my implementation plan base on only a couple of weeks of research. I’m sure my arguments and plan will evolve over time as my Rapa journey unfolds.
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Thank you. Yes, I am on week 3. I started with 6 mg but I had some minor side effects (petechiae) so I have gone to 4 mg and 2 mg. I will work back up when things stabilize.
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Let me add that personally, I plan to continue weekly rapa for about 3-4 weeks after my surgery, depending on how fully my M3M wound sites heal. But once I consistently hit side effects at what I presume will be the roughly same dose range, I’m going to do a washout and retest to really nail down Cmax and Ctrough, in my case.
I repeat I simply do not know what is optimal dosing if we assume rapa is beneficial in humans and all animal studies translate. It might not and even if they do, many don’t realize the subtleties involved with mice studies that literally drove Dr. Miller to develop their own protocol for reproducibility. And even then, there are a few minor subtleties to account for that the ITP doesn’t ie gut bacteria differences.
But I have some clues.
I was going with phase 1b style dose escalation (I use modified Fibonacci schema originally due to lack of precise data, but not starting at LD10) simply because blood levels are highly individual and we already know ultra-high doses aren’t lethal and probably still beneficial. My main goal is to figure out pharmacokinetics and side effects for my individual situation. We already have human data that intersubject variability in rapa levels is 45% and intrasubject variability is 38%.
As for dosing frequency, we don’t even know what’s the best in mice. Maybe you are right about your dosing schedule but I have no empirical evidence in animal studies to go off it being beneficial and there is empirical evidence against it. I’ve sort of alluded to it before, but let me explain further.
My approach is I’m running the odds favoring a high Cmax approach with the least side effects as far as I can tell - pretty similar to Dr. B’s stated approach with some minor differences, but I got to this independently from literature review and then after taking different views in consideration with more literature review. I may have some modifications in the future.
Here’s what the evidence is so far for mice is at high Cmax when you look at intraperitoneal 8 mg/kg daily albeit not much comparable to NIA ITP mice, we have evidence of ultra-high dose having a beneficial effect.
This means a 6 mg per week dose could be 5-10x off for maximum benefit for lifespan and maybe 60 mg per week is optimum for maximum lifespan for all I know, considering the NIA ITP showed 3x higher dose showed a greater increase in lifespan. We don’t know optimal Cmax and Cmin trough, but presumably, if I go high up ie 12-65 mg, I would start spacing out frequency aggressively to keep Cmin trough lower to reduce the risk of a potentially too high trough (ie impaired wound healing and other critical functions that cannot be done with higher rapamycin troughs because rapa abolishes signaling - see: Effect of Rapamycin on Wound Healing: An Experimental Study - ScienceDirect), not just because of the subjective experience of Dr. Green’s patients. It obviously changes less AUC - but I’m thinking more on the lines of reward vs risk for my own risk tolerance based on empirical data.
As for why I still favor a high pulse dose with high Cmax, Let me point out one of the many reasons why crossing the BBB is possibly important that isn’t seen in some of the lower Cmax in animals:
I would also point out we know impaired wound healing and stem cells in kidney transplant patients from continuous dosing hence I would rather keep Cmin low with enough buffer. We also know that so-called “bad” IGF-1 and “pro-aging” BCAAs like leucine are important for muscle satellite cells (stem cells), but we probably can’t do that with a high Cmin rapamycin level: Insulin-like growth factor-1 (IGF-1) and leucine activate pig myogenic satellite cells through mammalian target of rapamycin (mTOR) pathway - PubMed
I also would point out that testing biomarkers and monitoring symptoms are nice to haves, but they are not adequate for my risk tolerance. At some point, I might consider giving biomarkers using skin biopsy a try just to be sure. I think this is going to be important because if I was ever at high risk for cancer - I’d probably take more potential risk with higher levels of mTORC2i.
I also will point out that if one actually read the NIA ITP results carefully - instead of just the abstract and median lifespans on the graphs - the mice with the highest dose (so far) had the highest elevated serum glucose and highest median lifespan!
All these “mTORC2i = bad” folks will have to reconcile this apparent empirical “benevolent pseudo-diabetes” phenomenon with their assumptions based on diseased populations. I am not saying mTORC2i must be “good” btw - I am thinking severe mTORC2i should be avoided based on the uncertainty involved, but mild mTORC2i does not seem extremely harmful in the short run, perhaps possibly beneficial, and seems to normalize downwards after some time. It appears to me that hyperglycemia is reversible, unlike diabetes, so it’s a different process. This is based on my assumption of my low average baseline fasting insulin and CGM glucose low average baseline to begin with.
I’ll also mention minimal infection vulnerability is important and I think some here get too cavalier about it. But that’s for another discussion.
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Why not just take Metformin with the Rapamycin to manage the pseudo diabetes?
I take acarbose (and/or multiple acarbose-like nutraceuticals from diet), do exercise, and basically mild CR (from TRF) because those combinations appear to work with rapamycin from empirical evidence - not because it counters hyperglycemia.
I prefer acarbose partly because it’s much less off-target stuff than metformin. Easier to pinpoint effects with a “cleaner” drug and avoid drug interactions from non-systemic. Plus, the combination had the best results in ITP.
The literature is packed with over-interpretation of pseudo-diabetes as “bad” though - that’s why you have people claiming it must be “managed”. Too premature to say that transient mild hyperglycemia (grade 1-2 to be more precise) is worth aggressively treating for, especially when the mice with the highest glucose lived the longest. I think it’s simply worth ignoring since over the long run there are adaptations.
Ketogenic diets also go down the same overinterpretation process.
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In making these decisions it’s important to understand the pharmacokinetics of the drugs. Here’s a recent summary
https://onlinelibrary.wiley.com/doi/10.1111/jcpt.13753
Some takeaways:
- Due to high first pass metabolism, rapamycin is about 20% bioavailable. Low.
Of interest, everolimus is even worse at only 16%. - Rapamycin has excellent tissue and organ distribution. In blood 95% of it goes to red blood cells.
- High fat meal increases bioavailability by 35%.
Daily grapefruit juice increases it by over 3 fold. - Trough levels >15ug are associated with low platelets and elevated lipids.
- Everolimus in particular has enormous, 85% inter- individual variability.
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@tongMD Well thought out, as usual. Its been years since I have had to look a dosing curves and easier to just consult my Pharm D’s. Am I wrong in that most side effects occur in the peak levels? It seems rare to pick a large one time dose over dosing spread out over a longer period. Even Prozac, that I believe has an even a longer half life than Rapa, is dosed daily. Troughs for Rapa make sense with mTOR2 inhibition - so getting the trough sub-therapeutic would be a goal for longevity people.
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I am leaning this way too in the context of very healthy persons, able to withstand the hormesis. Remember most all of the human rapamycin ADE data is from cancer/transplant cohorts…a likely very different calculus.
My approach is high AUC without side effects, which is connected to the entire pharmacokinetic curve, not just Cmax or trough.
What are you measuring, rapamycin tissue levels and/or mTOR phosphorylation markers? There have been several pharmacodynamic tissue studies showing poor correlation to dose, rapamycin tissue level, mTOR inhibition markers, and primary end point efficacy.
How would you be able to prophesize your “risk for cancer”, other than say singular known causative genes? Isn’t it very much the case that THE longevity benefits of taking rapamycin are prophylaxis…to defer/delay cancer a priori? You cannot wait until you have a cancer diagnosis…rapamycin hasn’t shown great efficacy in significant lifespan extension in clinical cancer trials.
Rapamycin extends murine lifespan but has limited effects on aging
I agree with you here…“a different process”. Mild mTOR2 dsyregulation is now thought to be very much associated with cancer suppression pathways, and elevated glucose is a hormetic insulin signalling perturbation, NOT related to classic metabolic syndrome and pancreatic beta-cell dysfunction.
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